This invention relates to a novel series of 1,5-disubstituted-2-pyrrolidones which are prostaglandin-like in chemical structure and biological character, the process for making such 2-pyrrolidones and synthetic intermediates employed in these processes.
The C.sub.20 unsaturated fatty acids, known as prostaglandins, form a large family of naturally-occurring compounds. These molecules may have as many as fine asymmetric centers and are present in and evoke response from a diversity of biological tissues. An example of a particular species of the prostaglandin E genera is PGE.sub.2 pictured below. ##STR1##
According to the notation usually employed to describe the stereochemistry of prostaglandins, a heavy solid line represents the .beta. configuration which is defined as a bond coming up out of the plane of the paper and toward the reader. In a like manner, a dotted or hashed line represents the .alpha. configuration which is defined as a bond goin behind the plane of the paper and away from the reader. Thus, the configuration of the prostaglandin E.sub.2, pictured above, is .alpha. at carbon 8 and .beta. at carbon 12. [S. Bergstrom, et al., Acta. Chem. Scand., 16, 501 (1962)].
By the same terminology, a wavy line represents a mixture of the two forms .alpha. and .beta.. Thus, a 2-pyrrolidone of the structure: ##STR2## represents a mixture of the epimers ##STR3## and ##STR4##
By reference to the pyrrolidone of structure II and prostaglandin E.sub.2 shown above, a stereochemical comparison can be made between the two sets of compounds. The stereochemistry at positions 12 and 15 is the same in both types but that at position 8 is different. That is, the configuration of the C8-C7 bond of the prostaglandin E is .alpha., but that of the N8-C7 bond is in the plane of the paper according to the representation of the drawing above. Another way to represent the above two examples which will develop a better appreciation of this difference in configuration is the edge-on drawing below: ##STR5## where A and B stand for the two side chains of the examples. Here the illustration depicts the eclipsing of the A-C8 bond with the C12-H bond and the eclipsing of the C12-B bond with the C8-H bond in the case of the prostaglandin E and the bisecting position of the A-N8 bond with respect to the dihedral angle formed by B-C12-H in the case of the pyrrolidone. This difference in conformation is a result of the planarity generated by the amide moiety of the pyrrolidone. ["Basic Principles of Organic Chemistry", J. D. Roberts and M. C. Caserio, W. A. Benjamin, New York, 1965, p. 674]
A systematic name for a 1,5-disubstituted-2-pyrrolidone of the structure: ##STR6## is 1-(6'-carboxyhexyl)-5.beta.-(3".alpha.-hydroxyoct-1"-enyl)-2-pyrrolidone a nd it also can be named as a derivative of 11-desoxyprostaglandin E.sub.1 ; that is, 8-aza-11-desoxy PGE.sub.1.
The corresponding 8-aza-11-desoxy PGE.sub.2 compound has the structure: ##STR7## where the single bond between C2' and C3' has been replaced by a double bond. The corresponding 8-aza-11-desoxy PGE.sub.0 compound has the structure: ##STR8## where the double bond between C1" and C2" has been replaced by a single bond.
The above pyrrolidones have several centers of asymmetry, and can exist in the racemic (optically inactive) form and in either of the two enantiomeric (optically active) forms, i.e. the dextrorotatory (D) and levorotatory (L) forms. As drawn above, each pyrrolidone structure represents the particular active form or enantiomer which is derivable in part from D-glutamic acid. The mirror image or optical antipode of each of the above structures represents the other enantiomer of that pyrrolidone and is derivable in part from L-glutamic acid.
For instance, the optical antipode of 1-(6'-carboxyhexyl)-5.beta.-(3".alpha.-hydroxyoct-1"-enyl)-2-pyrrolidone is drawn as: ##STR9## and is called 1-(6'-carboxyhexyl)-5.alpha.-(3".beta.-hydroxyoct-1"-enyl)-2-pyrrolidone.
As pointed out earlier, substitution of a nitrogen for the carbon at C8 causes a dramatic change in the three dimensional conformation of the resultant prostaglandin. Because structure is related to biological activity and often a subtle change in structure such as a conformational change will have a profound effect upon the biological activity, such molecular modification of prostaglandins by substitution of heteroatoms has been investigated recently. Most compounds are attempts at investigation of heteroatom substitutions at the C9 and C11 prostaglandin positions and include such examples as 9-oxaprostaglandins (I. Vlattas, Tetrahedron Let., 4455 (1974)]; 11-oxaprostaglandins [A. Fougerousse, Tetrahedron Let., 3983 (1974)] and S. Hanessian et al., Tetrahedron Let., 3983 (1974) and 9-thiaprostaglandins [I. Vlattas, Tetrahedron, Let., 4459 (1974)].
Two 8-aza-11-desoxy prostaglandin E's with the natural .omega.-side chain, that is, compounds with the aza substitution at C8 of 11-desoxy prostaglandin E.sub.1 and E.sub.2 have also been reported in the literature [G. Bolliger and J. M. Muchowski, Tetrahedron Let., 2931 (1975) (Aug. 1975); and J. W. Bruin, et al., Tetrahedron Let., 4599 (1975)]. These examples of pyrrolidone compounds are outside of the scope of the present invention which presents a higher order of complexity and molecular variation at the C1 prostaglandin position and in the .omega.-side chain. Relatively little biological activity is reported for these literature examples and they can be contrasted in form and in molecular complexity with the novel compounds of the present invention.
The natural prostaglandins and many of their derivatives such as the esters, acylates, and pharmacologically acceptable salts, are extremely potent inducers of various biological responses [D. E. Wilson, Arch. Intern. Med., 133 (29) (1974)] in tissues composed of smooth muscle such as those of the cardiovascular, pulmonary, gastrointestinal and reproductive systems, in cellular tissues such as those of the central nervous, hematologic, reproductive, gastrointestinal, pulmonary, nephritic, epidermal, cardiovascular and adipose systems and also operate as mediators in the process of homeostasis. With such a wide range of responses, it is apparent that the prostaglandins are involved in basic biological processes of the cell. Indeed, this basic implication of prostaglandins is supported by the fact that they can be found in cellular tissue of almost all animal organisms.
Often on such a cellular level the actions of closely related natural prostaglandins may be opposite. For instance, the effect of PGE.sub.2 on human platelets is enhancement of aggregation while that of PGE.sub.1 is inhibition of aggregation.
Such contrasting effects may also be observed at the tissue level. For instance, in vivo PGE.sub.2 action on the cardiovascular system of mammals manifests itself by causing hypotension while the in vivo action of PGF.sub.2.alpha. is hypertension [J. B. Lee, Arch. Intern. Med., 133 56 (1974)]. However, the ability to predict the biological action of prostaglandin classes based upon such observations is largely illusory at present. For instance, while the cardiovascular actions of PGE.sub.2 and PGF.sub.2.alpha. are opposite as described above, their in vivo or in vitro action on mammalian uterine smooth muscle is the same and is stimulatory (causes contraction) [H. R. Behrman, et al., Arch. Intern. Med., 133 77 (1974)].
In the preparation of synthetic pharmaceutical agents, among the principal objects is the development of compounds which are highly selective in their pharmacological activity and which have an increased duration of activity over their naturally occurring relatives. In a series of compounds which is similar to the naturally-occurring prostaglandins, increasing selectivity of a single compound usually involves the enhancement of one prostaglandin-like physiological effect and the diminution of the others. By increasing the selectivity, one would alleviate the severe side effects frequently observed following administration of the natural prostaglandins; for example, those gastrointestinal side effects of diarrhea and emesis or cardiovascular side effects when bronchodilator effects are desired. Recent developments directed toward an increase of biological selectivity include the 11-desoxy prostaglandins [N. H. Anderson, Arch. Intern. Med., 133, 30 (1974) Review], 2-descarboxy-2-(tetrazol-5-yl)-11-desoxy-15-substituted-.omega.-pentanorpr ostaglandins (M. R. Johnson et al., U.S. Pat. No. 3,932,389) where certain modifications are cited as producing selective vasodilator, antiulcer, antifertility, bronchodilator and antihypertensive properties, 16-phenoxy-16-.omega.-tetranor prostaglandins having antifertility activity (U.K. Pat. No. 1,350,971) and 1-imide and 1-sulfonimide prostaglandins (U.S. Pat. No. 3,954,741).